Primary sclerosing cholangitis (PSC) is a chronic inflammatory liver disease of unknown etiology, primarily targeting cholangiocytes at any portion of the biliary tree. No effective medical treatments are currently available. A unique feature of PSC is its close association (about 80%) with inflammatory bowel disease (IBD), mainly ulcerative colitis (UC). As in many chronic inflammatory conditions, cancer development can complicate PSC, accounting for >40% of deaths. Cholangiocarcinoma (CCA), gallbladder carcinoma (GBC) and colorectal carcinoma (CRC) have been variably associated to PSC, with a prevalence up to 13-14%. The risk of cancer is one of the most challenging issues in the management of PSC; it raises several questions about cancer surveillance, early diagnosis, prevention and treatment. Key Messages: Among the different cancers complicating PSC, CCA is the most relevant, because it is more frequent (incidence of 0.5-1.5%) and because the prognosis is poor (5-year survival <10%). Early diagnosis of CCA in PSC can be difficult because lesions may not be evident in radiological studies. Surgical resection provides disappointing results; liver transplantation combined with neoadjuvant chemoradiotherapy is being proposed, but this approach is limited to a highly selected group of patients and is available only in a few specialized centers. Similar to CCA, GBC carries a dismal prognosis. Since it is difficult to discriminate GBC from other gallbladder abnormalities, cholecystectomy has been proposed in all gallbladder lesions detected in PSC, regardless of their size. CRC is a frequent complication of PSC associated to UC; its incidence steadily increases with time of colitis, reaching up to 20-30% of the patients after 20 years. Colonoscopy with extensive histologic sampling at an annual/biannual interval is an effective surveillance strategy. However, when dysplastic lesions are detected, preemptive proctocolectomy should be considered. Conclusions: PSC may be regarded as paradigmatic of the sequence leading from chronic inflammatory epithelial damage to neoplastic transformation. Understanding the molecular mechanisms regulating this pathogenetic sequence, may improve strategies of disease surveillance and cancer prevention and treatment. PSC is a chronic inflammatory cholangiopathy of unknown etiology but likely immune-mediated, characterized by peribiliary inflammation and fibrosis leading to strictures in any portion (intra- and/or extrahepatic) of the bile duct system. No effective medical treatments are currently available. A unique feature of PSC is the close association (about 80%) with IBD, mainly UC, often diagnosed before PSC (PSC/UC). As in other chronic inflammatory diseases, development of malignancies is a feared complication of PSC.

Keywords:
Cholangiocyte, Cholangiocarcinoma, Colorectal cancer, Gallbladder carcinoma, Ulcerative colitis
1.
Fevery J, Henckaerts L, Van Oirbeek R, Vermeire S, Rutgeerts P, Nevens F, Van Steenbergen W: Malignancies and mortality in 200 patients with primary sclerosering cholangitis: a long-term single-centre study. Liver Int 2012;32:214-222.
2.
Bergquist A, Ekbom A, Olsson R, Kornfeldt D, Lööf L, Danielsson A, Hultcrantz R, Lindgren S, Prytz H, Sandberg-Gertzén H, Almer S, Granath F, Broomé U: Hepatic and extrahepatic malignancies in primary sclerosing cholangitis. J Hepatol 2002;36:321-327.
3.
Bergquist A, Said K, Broomé U: Changes over a 20-year period in the clinical presentation of primary sclerosing cholangitis in Sweden. Scand J Gastroenterol 2007;42:88-93.
4.
Burak K, Angulo P, Pasha TM, Egan K, Petz J, Lindor KD: Incidence and risk factors for cholangiocarcinoma in primary sclerosing cholangitis. Am J Gastroenterol 2004;99:523-526.
5.
Darwish Murad S, Kim WR, Therneau T, Gores GJ, Rosen CB, Martenson JA, Alberts SR, Heimbach JK: Predictors of pretransplant dropout and posttransplant recurrence in patients with perihilar cholangiocarcinoma. Hepatology 2012;56:972-981.
6.
Boberg KM, Bergquist A, Mitchell S, Pares A, Rosina F, Broomé U, Chapman R, Fausa O, Egeland T, Rocca G, Schrumpf E: Cholangiocarcinoma in primary sclerosing cholangitis: risk factors and clinical presentation. Scand J Gastroenterol 2002;37:1205-1211.
7.
Chalasani N, Baluyut A, Ismail A, Zaman A, Sood G, Ghalib R, McCashland TM, Reddy KR, Zervos X, Anbari MA, Hoen H: Cholangiocarcinoma in patients with primary sclerosing cholangitis: a multicenter case-control study. Hepatology 2000;31:7-11.
8.
Claessen MM, Vleggaar FP, Tytgat KM, Siersema PD, van Buuren HR: High lifetime risk of cancer in primary sclerosing cholangitis. J Hepatol 2009;50:158-164.
9.
Angulo P, Maor-Kendler Y, Lindor KD: Small-duct primary sclerosing cholangitis: a long-term follow-up study. Hepatology 2002;35:1494-1500.
10.
Clayton RA, Clarke DL, Currie EJ, Madhavan KK, Parks RW, Garden OJ: Incidence of benign pathology in patients undergoing hepatic resection for suspected malignancy. Surgeon 2003;1:32-38.
11.
Fevery J, Verslype C: An update on cholangiocarcinoma associated with primary sclerosing cholangitis. Curr Opin Gastroenterol 2010;26:236-245.
12.
Moreno Luna LE, Gores GJ: Advances in the diagnosis of cholangiocarcinoma in patients with primary sclerosing cholangitis. Liver Transpl 2006;12(11 suppl 2):S15-S19.
13.
Charatcharoenwitthaya P, Enders FB, Halling KC, Lindor KD: Utility of serum tumor markers, imaging, and biliary cytology for detecting cholangiocarcinoma in primary sclerosing cholangitis. Hepatology 2008;48:1106-1117.
14.
Levy C, Lymp J, Angulo P, Gores GJ, Larusso N, Lindor KD: The value of serum CA 19-9 in predicting cholangiocarcinomas in patients with primary sclerosing cholangitis. Dig Dis Sci 2005;50:1734-1740.
15.
Sinakos E, Saenger AK, Keach J, Kim WR, Lindor KD: Many patients with primary sclerosing cholangitis and increased serum levels of carbohydrate antigen 19-9 do not have cholangiocarcinoma. Clin Gastroenterol Hepatol 2011;9:434-439.e1.
16.
Wannhoff A, Hov JR, Folseraas T, Rupp C, Friedrich K, Anmarkrud JA, Weiss KH, Sauer P, Schirmacher P, Boberg KM, Stremmel W, Karlsen TH, Gotthardt DN: FUT2 and FUT3 genotype determines CA19-9 cut-off values for detection of cholangiocarcinoma in patients with primary sclerosing cholangitis. J Hepatol 2013;59:1278-1284.
17.
Nehls O, Gregor M, Klump B: Serum and bile markers for cholangiocarcinoma. Semin Liver Dis 2004;24:139-154.
18.
Trikudanathan G, Navaneethan U, Njei B, Vargo JJ, Parsi MA: Diagnostic yield of bile duct brushings for cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc 2014;79:783-789.
19.
Siqueira E, Schoen RE, Silverman W, Martin J, Rabinovitz M, Weissfeld JL, Abu-Elmaagd K, Madariaga JR, Slivka A: Detecting cholangiocarcinoma in patients with primary sclerosing cholangitis. Gastrointest Endosc 2002;56:40-47.
20.
Navaneethan U, Njei B, Venkatesh PG, Vargo JJ, Parsi MA: Fluorescence in situ hybridization for diagnosis of cholangiocarcinoma in primary sclerosing cholangitis: a systematic review and meta-analysis. Gastrointest Endosc 2014;79:943-950.e3.
21.
Barr Fritcher EG, Kipp BR, Voss JS, Clayton AC, Lindor KD, Halling KC, Gores GJ: Primary sclerosing cholangitis patients with serial polysomy fluorescence in situ hybridization results are at increased risk of cholangiocarcinoma. Am J Gastroenterol 2011;106:2023-2028.
22.
Razumilava N, Gores GJ, Lindor KD: Cancer surveillance in patients with primary sclerosing cholangitis. Hepatology 2011;54:1842-1852.
23.
Sangfelt P, Sundin A, Wanders A, Rasmussen I, Karlson BM, Bergquist A, Rorsman F: Monitoring dominant strictures in primary sclerosing cholangitis with brush cytology and FDG-PET. J Hepatol 2014;61:1352-1357.
24.
Ahrendt SA, Pitt HA, Nakeeb A, Klein AS, Lillemoe KD, Kalloo AN, Cameron JL: Diagnosis and management of cholangiocarcinoma in primary sclerosing cholangitis. J Gastrointest Surg 1999;3:357-367; discussion 367-368.
25.
Rea DJ, Heimbach JK, Rosen CB, Haddock MG, Alberts SR, Kremers WK, Gores GJ, Nagorney DM: Liver transplantation with neoadjuvant chemoradiation is more effective than resection for hilar cholangiocarcinoma. Ann Surg 2005;242:451-458; discussion 458-461.
26.
Heimbach JK, Gores GJ, Haddock MG, Alberts SR, Pedersen R, Kremers W, Nyberg S, Ishitani MB, Rosen CB: Predictors of disease recurrence following neoadjuvant chemoradiotherapy and liver transplantation for unresectable perihilar cholangiocarcinoma. Transplantation 2006;82:1703-1707.
27.
Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC: Precancerous bile duct pathology in end-stage primary sclerosing cholangitis, with and without cholangiocarcinoma. Am J Surg Pathol 2010;34:27-34.
28.
Boberg KM, Jebsen P, Clausen OP, Foss A, Aabakken L, Schrumpf E: Diagnostic benefit of biliary brush cytology in cholangiocarcinoma in primary sclerosing cholangitis. J Hepatol 2006;45:568-574.
29.
European Association for the Study of the Liver: EASL clinical practice guidelines: management of cholestatic liver disease. J Hepatol 2009;51:237-267.
30.
Chapman R, Fevery J, Kalloo A, Nagorney DM, Boberg KM, Shneider B, Gores GJ; American Association for the Study of Liver Diseases: Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;51:660-678.
31.
Gores GJ: Early detection and treatment of cholangiocarcinoma. Liver Transpl 2000;6(6 suppl 2):S30-S34.
32.
Trilianos P, Selaru F, Li Z, Gurakar A: Trends in pre-liver transplant screening for cholangiocarcinoma among patients with primary sclerosing cholangitis. Digestion 2014;89:165-173.
33.
Prytz H, Keiding S, Björnsson E, Broomé U, Almer S, Castedal M, Munk OL: Dynamic FDG-PET is useful for detection of cholangiocarcinoma in patients with PSC listed for liver transplantation. Hepatology 2006;44:1572-1580.
34.
Said K, Glaumann H, Bergquist A: Gallbladder disease in patients with primary sclerosing cholangitis. J Hepatol 2008;48:598-605.
35.
Yang HL, Sun YG, Wang Z: Polypoid lesions of the gallbladder: diagnosis and indications for surgery. Br J Surg 1992;79:227-229.
36.
Lewis JT, Talwalkar JA, Rosen CB, Smyrk TC, Abraham SC: Prevalence and risk factors for gallbladder neoplasia in patients with primary sclerosing cholangitis: evidence for a metaplasia-dysplasia-carcinoma sequence. Am J Surg Pathol 2007;31:907-913.
37.
Zielinski MD, Atwell TD, Davis PW, Kendrick ML, Que FG: Comparison of surgically resected polypoid lesions of the gallbladder to their pre-operative ultrasound characteristics. J Gastrointest Surg 2009;13:19-25.
38.
Sugiyama M, Atomi Y, Kuroda A, Muto T, Wada N: Large cholesterol polyps of the gallbladder: diagnosis by means of US and endoscopic US. Radiology 1995;196:493-497.
39.
Azuma T, Yoshikawa T, Araida T, Takasaki K: Differential diagnosis of polypoid lesions of the gallbladder by endoscopic ultrasonography. Am J Surg 2001;181:65-70.
40.
Leung UC, Wong PY, Roberts RH, Koea JB: Gall bladder polyps in sclerosing cholangitis: does the 1-cm rule apply? ANZ J Surg 2007;77:355-357.
41.
Rosen CB, Nagorney DM, Wiesner RH, Coffey RJ Jr, LaRusso NF: Cholangiocarcinoma complicating primary sclerosing cholangitis. Ann Surg 1991;213:21-25.
42.
Becker NS, Rodriguez JA, Barshes NR, O'Mahony CA, Goss JA, Aloia TA: Outcomes analysis for 280 patients with cholangiocarcinoma treated with liver transplantation over an 18-year period. J Gastrointest Surg 2008;12:117-122.
43.
Boonstra K, Beuers U, Ponsioen CY: Epidemiology of primary sclerosing cholangitis and primary biliary cirrhosis: a systematic review. J Hepatol 2012;56:1181-1188.
44.
Rasmussen HH, Fallingborg JF, Mortensen PB, Vyberg M, Tage-Jensen U, Rasmussen SN: Hepatobiliary dysfunction and primary sclerosing cholangitis in patients with Crohn's disease. Scand J Gastroenterol 1997;32:604-610.
45.
Fausa O, Schrumpf E, Elgjo K: Relationship of inflammatory bowel disease and primary sclerosing cholangitis. Semin Liver Dis 1991;11:31-39.
46.
Soetikno RM, Lin OS, Heidenreich PA, Young HS, Blackstone MO: Increased risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis: a meta-analysis. Gastrointest Endosc 2002;56:48-54.
47.
Broomé U, Bergquist A: Primary sclerosing cholangitis, inflammatory bowel disease, and colon cancer. Semin Liver Dis 2006;26:31-41.
48.
Braden B, Halliday J, Aryasingha S, Sharifi Y, Checchin D, Warren BF, Kitiyakara T, Travis SP, Chapman RW: Risk for colorectal neoplasia in patients with colonic Crohn's disease and concomitant primary sclerosing cholangitis. Clin Gastroenterol Hepatol 2012;10:303-308.
49.
de Valle MB, Björnsson E, Lindkvist B: Mortality and cancer risk related to primary sclerosing cholangitis in a Swedish population-based cohort. Liver Int 2012;32:441-448.
50.
Boonstra K, Weersma RK, van Erpecum KJ, Rauws EA, Spanier BW, Poen AC, van Nieuwkerk KM, Drenth JP, Witteman BJ, Tuynman HA, Naber AH, Kingma PJ, van Buuren HR, van Hoek B, Vleggaar FP, van Geloven N, Beuers U, Ponsioen CY; EpiPSCPBC Study Group: Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis. Hepatology 2013;58:2045-2055.
51.
Boonstra K, van Erpecum KJ, van Nieuwkerk KM, Drenth JP, Poen AC, Witteman BJ, Tuynman HA, Beuers U, Ponsioen CY: Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease. Inflamm Bowel Dis 2012;18:2270-2276.
52.
Eaton JE, Talwalkar JA, Lazaridis KN, Gores GJ, Lindor KD: Pathogenesis of primary sclerosing cholangitis and advances in diagnosis and management. Gastroenterology 2013;145:521-536.
53.
Rudolph G, Gotthardt D, Kloeters-Plachky P, Rost D, Kulaksiz H, Stiehl A: In PSC with dominant bile duct stenosis, IBD is associated with an increase of carcinomas and reduced survival. J Hepatol 2010;53:313-317.
54.
Torres J, Pineton de Chambrun G, Itzkowitz S, Sachar DB, Colombel JF: Review article: colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease. Aliment Pharmacol Ther 2011;34:497-508.
55.
Singh S, Edakkanambeth Varayil J, Loftus EV Jr, Talwalkar JA: Incidence of colorectal cancer after liver transplantation for primary sclerosing cholangitis: a systematic review and meta-analysis. Liver Transpl 2013;19:1361-1369.
56.
Sint Nicolaas J, de Jonge V, Steyerberg EW, Kuipers EJ, van Leerdam ME, Veldhuyzen-van Zanten SJ: Risk of colorectal carcinoma in post-liver transplant patients: a systematic review and meta-analysis. Am J Transplant 2010;10:868-876.
57.
Loftus EV Jr, Aguilar HI, Sandborn WJ, Tremaine WJ, Krom RA, Zinsmeister AR, Graziadei IW, Wiesner RH: Risk of colorectal neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis following orthotopic liver transplantation. Hepatology 1998;27:685-690.
58.
Brentnall TA, Haggitt RC, Rabinovitch PS, Kimmey MB, Bronner MP, Levine DS, Kowdley KV, Stevens AC, Crispin DA, Emond M, Rubin CE: Risk and natural history of colonic neoplasia in patients with primary sclerosing cholangitis and ulcerative colitis. Gastroenterology 1996;110:331-338.
59.
Eaton JE, Smyrk TC, Imam M, Pardi DS, Loftus EV Jr, Owens VL, Talwalkar JA: The fate of indefinite and low-grade dysplasia in ulcerative colitis and primary sclerosing cholangitis colitis before and after liver transplantation. Aliment Pharmacol Ther 2013;38:977-987.
60.
Tung BY, Emond MJ, Haggitt RC, Bronner MP, Kimmey MB, Kowdley KV, Brentnall TA: Ursodiol use is associated with lower prevalence of colonic neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Ann Intern Med 2001;134:89-95.
61.
Pardi DS, Loftus EV Jr, Kremers WK, Keach J, Lindor KD: Ursodeoxycholic acid as a chemopreventive agent in patients with ulcerative colitis and primary sclerosing cholangitis. Gastroenterology 2003;124:889-893.
62.
Wolf JM, Rybicki LA, Lashner BA: The impact of ursodeoxycholic acid on cancer, dysplasia and mortality in ulcerative colitis patients with primary sclerosing cholangitis. Aliment Pharmacol Ther 2005;22:783-788.
63.
Singh S, Khanna S, Pardi DS, Loftus EV Jr, Talwalkar JA: Effect of ursodeoxycholic acid use on the risk of colorectal neoplasia in patients with primary sclerosing cholangitis and inflammatory bowel disease: a systematic review and meta-analysis. Inflamm Bowel Dis 2013;19:1631-1638.
64.
Eaton JE, Silveira MG, Pardi DS, Sinakos E, Kowdley KV, Luketic VA, Harrison ME, McCashland T, Befeler AS, Harnois D, Jorgensen R, Petz J, Lindor KD: High-dose ursodeoxycholic acid is associated with the development of colorectal neoplasia in patients with ulcerative colitis and primary sclerosing cholangitis. Am J Gastroenterol 2011;106:1638-1645.
65.
Lindberg BU, Broomé U, Persson B: Proximal colorectal dysplasia or cancer in ulcerative colitis. The impact of primary sclerosing cholangitis and sulfasalazine: results from a 20-year surveillance study. Dis Colon Rectum 2001;44:77-85.
66.
Harnois DM, Gores GJ, Ludwig J, Steers JL, LaRusso NF, Wiesner RH: Are patients with cirrhotic stage primary sclerosing cholangitis at risk for the development of hepatocellular cancer? J Hepatol 1997;27:512-516.
67.
Zenouzi R, Weismüller TJ, Hübener P, Schulze K, Bubenheim M, Pannicke N, Weiler-Normann C, Lenzen H, Manns MP, Lohse AW, Schramm C: Low risk of hepatocellular carcinoma in patients with primary sclerosing cholangitis with cirrhosis. Clin Gastroenterol Hepatol 2014;12:1733-1738.
68.
Rizvi S, Borad MJ, Patel T, Gores GJ: Cholangiocarcinoma: molecular pathways and therapeutic opportunities. Semin Liver Dis 2014;34:456-464.
69.
Spirlì C, Fabris L, Duner E, Fiorotto R, Ballardini G, Roskams T, Larusso NF, Sonzogni A, Okolicsanyi L, Strazzabosco M: Cytokine-stimulated nitric oxide production inhibits adenylyl cyclase and cAMP-dependent secretion in cholangiocytes. Gastroenterology 2003;124:737-753.
70.
Cadamuro M, Nardo G, Indraccolo S, Dall'Olmo L, Sambado L, Moserle L, Franceschet I, Colledan M, Massani M, Stecca T, Bassi N, Morton S, Spirli C, Fiorotto R, Fabris L, Strazzabosco M: Platelet-derived growth factor-D and Rho GTPases regulate recruitment of cancer-associated fibroblasts in cholangiocarcinoma. Hepatology 2013;58:1042-1053.
71.
Cadamuro M, Vismara M, Brivio S, Furlanetto A, Strazzabosco M, Fabris L: JNK signaling activated by platelet-derived growth factor-D (PDGF-D) stimulates secretion of vascular endothelial growth factor-C (VEGF-C) by cancer-associated fibroblasts to promote lymphangiogenesis and early metastasization in cholangiocarcinoma. J Hepatol 2015;62:S389.
72.
Ochsenkühn T, Bayerdörffer E, Meining A, Schinkel M, Thiede C, Nüssler V, Sackmann M, Hatz R, Neubauer A, Paumgartner G: Colonic mucosal proliferation is related to serum deoxycholic acid levels. Cancer 1999;85:1664-1669.
73.
Wohl P, Hucl T, Drastich P, Kamenar D, Spicak J, Honsova E, Sticova E, Lodererova A, Matous J, Hill M, Wohl P, Kucera M: Epithelial markers of colorectal carcinogenesis in ulcerative colitis and primary sclerosing cholangitis. World J Gastroenterol 2013;19:2234-2241.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.